Investigating brain connectivity heritability in a twin study using diffusion imaging data

Heritability of brain anatomical connectivity has been studied with diffusion-weighted imaging (DWI) mainly by modeling each voxel's diffusion pattern as a tensor (e.g., to compute fractional anisotropy), but this method cannot accurately represent the many crossing connections present in the brain. We hypothesized that different brain networks (i.e., their component fibers) might have different heritability and we investigated brain connectivity using High Angular Resolution Diffusion Imaging (HARDI) in a cohort of twins comprising 328 subjects that included 70 pairs of monozygotic and 91 pairs of dizygotic twins. Water diffusion was modeled in each voxel with a Fiber Orientation Distribution (FOD) function to study heritability for multiple fiber orientations in each voxel. Precision was estimated in a test-retest experiment on a sub-cohort of 39 subjects. This was taken into account when computing heritability of FOD peaks using an ACE model on the monozygotic and dizygotic twins. Our results confirmed the overall heritability of the major white matter tracts but also identified differences in heritability between connectivity networks. Inter-hemispheric connections tended to be more heritable than intra-hemispheric and cortico-spinal connections. The highly heritable tracts were found to connect particular cortical regions, such as medial frontal cortices, postcentral, paracentral gyri, and the right hippocampus.

Changes in white matter connectivity following therapy for anomia post stroke

Background. The majority of studies investigating the neural mechanisms underlying treatment-induced recovery in aphasia have focused on the cortical regions associated with language processing. However, the integrity of the white matter connecting these regions may also be crucial to understanding treatment mechanisms. Objective. This study investigated the integrity of the arcuate fasciculus (AF) and uncinate fasciculus (UF) before and after treatment for anomia in people with aphasia. Method. Eight people with aphasia received 12 treatment sessions to improve naming; alternating between phonologically-based and semantic-based tasks, with high angular resolution diffusion imaging conducted pre and post treatment. The mean generalized fractional anisotropy (GFA), a measure of fiber integrity, and number of fibers in the AF and UF were compared pre and post treatment, as well as with a group of 14 healthy older controls. Results. Pre treatment, participants with aphasia had significantly fewer fibers and lower mean GFA in the left AF compared with controls. Post treatment, mean GFA increased in the left AF to be statistically equivalent to controls. Additionally, mean GFA in the left AF pre and post treatment positively correlated with maintenance of the phonologically based treatment. No differences were found in the right AF, or the UF in either hemisphere, between participants with aphasia and controls, and no changes were observed in these tracts following treatment. Conclusions. Anomia treatments may improve the integrity of the white matter connecting cortical language regions. These preliminary results add to the understanding of the mechanisms underlying treatment outcomes in people with aphasia post stroke.

The tensor distribution function

Diffusion weighted magnetic resonance imaging is a powerful tool that can be employed to study white matter microstructure by examining the 3D displacement profile of water molecules in brain tissue. By applying diffusion-sensitized gradients along a minimum of six directions, second-order tensors (represented by three-by-three positive definite matrices) can be computed to model dominant diffusion processes. However, conventional DTI is not sufficient to resolve more complicated white matter configurations, e.g., crossing fiber tracts. Recently, a number of high-angular resolution schemes with more than six gradient directions have been employed to address this issue. In this article, we introduce the tensor distribution function (TDF), a probability function defined on the space of symmetric positive definite matrices. Using the calculus of variations, we solve the TDF that optimally describes the observed data. Here, fiber crossing is modeled as an ensemble of Gaussian diffusion processes with weights specified by the TDF. Once this optimal TDF is determined, the orientation distribution function (ODF) can easily be computed by analytic integration of the resulting displacement probability function. Moreover, a tensor orientation distribution function (TOD) may also be derived from the TDF, allowing for the estimation of principal fiber directions and their corresponding eigenvalues.

The three-dimensional hydrogen-bonded structures in the ammonium and sodium salt hydrates of 4-aminophenylarsonic acid

The structures of two hydrated salts of 4-aminophenylarsonic acid (p-arsanilic acid), namely ammonium 4-aminophenylarsonate monohydrate, NH4(+)·C6H7AsNO3(-)·H2O, (I), and the one-dimensional coordination polymer catena-poly[[(4-aminophenylarsonato-κO)diaquasodium]-μ-aqua], [Na(C6H7AsNO3)(H2O)3]n, (II), have been determined. In the structure of the ammonium salt, (I), the ammonium cations, arsonate anions and water molecules interact through inter-species N-H...O and arsonate and water O-H...O hydrogen bonds, giving the common two-dimensional layers lying parallel to (010). These layers are extended into three dimensions through bridging hydrogen-bonding interactions involving the para-amine group acting both as a donor and an acceptor. In the structure of the sodium salt, (II), the Na(+) cation is coordinated by five O-atom donors, one from a single monodentate arsonate ligand, two from monodentate water molecules and two from bridging water molecules, giving a very distorted square-pyramidal coordination environment. The water bridges generate one-dimensional chains extending along c and extensive interchain O-H...O and N-H...O hydrogen-bonding interactions link these chains, giving an overall three-dimensional structure. The two structures reported here are the first reported examples of salts of p-arsanilic acid.

Photoinduced DNA and Protein Cleavage Activity of Ferrocene-Conjugated Ternary Copper(II) Complexes

Ferrocene-conjugated ternary copper(II) complexes [Cu(L)(B)](ClO4)(2), where L is FcCH(2)N(CH2Py)(2) (Fc = (eta(5)-C5H4)Fe-II(eta(5)-C5H5)) and B is a phenanthroline base, viz., 2,2'-bipyridine (bpy, 1), 1, 10-phenanthroline (phen, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 3), and dipyrido[3,2-a:2',3'-c]phenazine (dppz, 4), have been synthesized and characterized by various spectroscopic and analytical techniques. The bpy complex 1, as its hexafluorophosphate salt, has been structurally characterized by X-ray crystallography. The molecular structure shows the copper(II) center having an essentially square-pyramidal coordination geometry in which L with a pendant ferrocenyl (Fc) moiety and bpy show respective tridentate and bidentate modes of binding to the metal center. The complexes are redox active, showing a reversible cyclic voltammetric response of the Fc(+)-Fc couple near 0.5 V vs SCE and a quasi-reversible Cu(II)-Cu(I) couple near 0.0 V. Complexes 2-4 show binding affinity to calf thymus (CT) DNA, giving binding constant (K-b) values in the range of 4.2 x 10(4) to 2.5 x 10(5) M-1. Thermal denaturation and viscometric titration data suggest groove binding and/or a partial intercalative mode of binding of the complexes to CT DNA. The complexes show good binding propensity to the bovine serum albumin (BSA) protein, giving K-BSA values of similar to 10(4) M-1 for the bpy and phen complexes and similar to 10(5) M-1 for the dpq and dppz complexes. Complexes 2-4 exhibit efficient chemical nuclease activity in the presence of 3-mercapto-propionic acid (MPA) as a reducing agent or hydrogen peroxide (H2O2) as an oxidizing agent. Mechanistic studies reveal formation of hydroxyl radicals as the reactive species. The dpq and dppz complexes are active in cleaving supercoiled (SC) pUC19 DNA on photoexposure to visible light of different wavelengths including red light using an argon-krypton mixed gas ion laser. Mechanistic investigations using various inhibitors reveal the fort-nation of hydroxyl radicals in the DNA photocleavage reactions. The dppz complex 4, which shows efficient photoioduced BSA cleavage activity, is a potent multifunctional model nuclease and protease in the chemistry of photodynamic therapy (PDT) of cancer.

Synthesis, crystal structures, DNA binding and cleavage activity of L-glutamine copper(II) complexes of heterocyclic bases

Ternary L-glutamine (L-gln) copper(II) complexes [Cu(L-gln)(B)(H2O)](X) (B = 2,2'-bipyridine (bpy), X = 0.5SO(4)(2-), 1; B = 1,10-phenanthroline (phen), X = ClO4-, 2) and [Cu(L-gln)(dpq)(ClO4)] (3) (dpq, dipyridoquinoxaline) are prepared and characterized by physicochemical methods. The DNA binding and cleavage activity of the complexes have been studied. Complexes 1-3 are structurally characterized by X-ray crystallography. The complexes show distorted square pyramidal (4+1) CuN3O2 coordination geometry in which the N,O-donor amino acid and the N, N-donor heterocyclic base bind at the basal plane with a H2O or perchlorate as the axial ligand. The crystal structures of the complexes exhibit chemically significant hydrogen bonding interactions besides showing coordination polymer formation. The complexes display a d-d electronic band in the range of 610-630 nm in aqueous-dimethylformamide (DMF) solution (9:1 v/v). The quasireversible cyclic voltammetric response observed near -0.1 V versus SCE in DMF-TBAP is assignable to the Cu(II)/Cu(I) couple. The binding affinity of the complexes to calf thymus (CT) DNA follows the order: 3 (dpq) > 2 (phen) >> 1 (bpy). Complexes 2 and 3 show DNA cleavage activity in dark in the presence of 3-mercaptopropionic acid (MPA) as a reducing agent via a mechanistic pathway forming hydroxyl radical as the reactive species. The dpq complex 3 shows efficient photoinduced DNA cleavage activity on irradiation with a monochromatic UV light of 365 nm in absence of any external reagent. The cleavage efficiency of the DNA minor groove binding complexes follows the order:3 > 2 >> 1. The dpq complex exhibits photocleavage of DNA on irradiation with visible light of 647.1 nm. Mechanistic data on the photo-induced DNA cleavage reactions reveal the involvement of singlet oxygen (O-1(2)) as the reactive species in a type-II pathway. (C) 2008 Elsevier B.V. All rights reserved.

Copper(II) Complexes of l-Arginine as Netropsin Mimics Showing DNA Cleavage Activity in Red Light

Copper(II) complexes [Cu(L-arg)(2)](NO3)(2) (1) and [Cu(L-arg)(B)Cl]Cl (2-5), where B is a heterocyclic base, namely, 2,2'-bipyridine (bpy, 2), 1,10-phenanthroline (phen, 3), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 4), and dipyrido[3,2-a:2',3'-c)phenazine (dppz, 5), are prepared and their DNA binding and photoinduced DNA cleavage activity studied. Ternary complex 3, structurally characterized using X-ray crystallography, shows a square-pyramidal (4 + 1) coordination geometry in which the N,O-donor L-arginine and N,N-donor 1,10-phenanthroline form the basal plane with one chloride at the elongated axial site. The complex has a pendant cationic guanidinium moiety. The one-electron paramagnetic complexes display a metal-centered d-d band in the range of 590-690 nm in aqueous DMF They show quasireversible cyclic voltammetric response due to the Cu(II)/Cu(I) couple in the range of -0.1 to -0.3 V versus a saturated calomel electrode in a DMF-Tris HCl buffer (pH 7.2). The DNA binding propensity of the complexes is studied using various techniques. Copper(II) bis-arginate 1 mimics the minor groove binder netropsin by showing preferential binding to the AT-rich sequence of double-strand (ds) DNA. DNA binding study using calf thymus DNA gives an order: 5 (L-arg-dppz) >= 1 (biS-L-arg) > 4 (L-arg-dpq) > 3 (L-arg-phen) >> 2 (L-arg-bpy). Molecular docking calculations reveal that the complexes bind through extensive hydrogen bonding and electrostatic interactions with ds-DNA. The complexes cleave supercoiled pUC19 DNA in the presence of 3-mercaptopropionic acid as a reducing agent forming hydroxyl ((OH)-O-center dot) radicals. The complexes show oxidative photoinduced DNA cleavage activity in UV-A light of 365 nm and red light of 647.1 nm (Ar-Kr mixed-gas-ion laser) in a metal-assisted photoexcitation process forming singlet oxygen (O-1(2)) species in a type-II pathway. All of the complexes, barring complex 2, show efficient DNA photocleavage activity. Complexes 4 and 5 exhibit significant double-strand breaks of DNA in red light of 647.1 nm due to the presence of two photosensitizers, namely, L-arginine and dpq or dppz in the molecules.

In search of inorganic nonlinear optical materials for second harmonic generation

In a search for inorganic oxide materials showing second-order nonlinear optical (NLO) susceptibility, we investigated several berates, silicates, and a phosphate containing trans-connected MO6, octahedral chains or MO5 square pyramids, where, M = d(0): Ti(IV), Nb(V), or Ta(V), Our investigations identified two new NLO structures: batisite, Na2Ba(TiO)(2)Si4O12, containing trans-connected TiO5 octahedral chains, and fresnoite, Ba2TiOSi2O7, containing square-pyramidal TiO5. Investigation of two other materials containing square-pyramidal TiO5 viz,, Cs2TiOP2O7 and Na4Ti2Si8O22. 4H(2)O, revealed that isolated TiO5, square pyramids alone do not cause a second harmonic generation (SHG) response; rather, the orientation of TiO5 units to produce -Ti-O-Ti-O- chains with alternating long and short Ti-O distances in the fresnoite structure is most likely the origin of a strong SHG response in fresnoite,

Geometry Of Proline And Hydroxyproline .1. An Analysis Of X-Ray Crystal-Structure Data

We have carried out an analysis of crystal structure data on prolyl and hydroxyprolyl moieties in small molecules. The flexibility of the pyrrolidine ring due to the pyramidal character of nitrogen has been defined in terms of two projection angles δ1 and δ2. The distribution of these parameters in the crystal structures is found to be consistent with results of the energy calculations carried out on prolyl moieties in our laboratory.

The Origin of Regioselectivity in a-Cleavage Reactions of Cyclopropenethiones: Potential Role of Pseudo-Jahn-Teller Effect in Substituted Cyclopropenyl Systems

Arylalkylcyclopropenethiones undergo highly regioselective photochemical a-cleavage via thioketene carbene intermediates, giving rise to products derived from the less stabilized carbene. UHF MIND0/3 calculations provide an insight into this unexpected regioselectivity. The nx* triplet of cyclopropenethione is calculated to have a highly unsymmetrical geometry with an elongated C-C bond, a delocalized thiaaUyl fragment, and a pyramidal radicaloid carbon (which eventually becomes the carbene center). From this molecular electronic structure, aryl group stabilization is expected to be more effective at the thiaallyl group rather than at the pyramidal radical center. Thus, the stability of the substituted triplet thione rather than that of the thioketene carbene determines the preferred regiochemistry of cleavage. The unusual structure of the cyclopropenethione triplet is suggested to be related to one of the Jahn-Teller distorted forms of the cyclopropenyl radical. An alternative symmetrical structure is adopted by the corresponding triplet of cyclopropenone, partly accounting for its differing photobehavior. A similar structural dichotomy is demonstrated for the corresponding radical anions as well.

Structure of 4-Hydroxymonophenylbutazone

4-Butyl-4-hydroxy-l-phenyl-3,5-pyrazolidinedione, ClaH16N20 a, Mr=248.3, monoclinic, P21/n, a = 22.357 (5), b = 5.014 (2), c = 11.350 (4)/~,, //=91.88(3) °, V=1272(1)A 3, Z=4, D,,=1.296(3), D x = 1.297 Mg m -3, 2(Cu Ka) = 1.5418/~, a = 0.777 mm -~, F(000) = 528, T= 293 K. Final R - 0.059 for 1668 observed reflections. The hetero nitrogen which carries the six-membered ring is planar in the structure while the other unsubstituted one is pyramidal. The five- and six-membered rings are almost coplanar. The crystal is made up of infinite columns of hydrogen-bonded molecules.

Cellular and network mechanisms generating spontaneous population events in the immature rat hippocampus

Distinct endogenous network events, generated independently of sensory input, are a general feature of various structures of the immature central nervous system. In the immature hippocampus, these type of events are seen as "giant depolarizing potentials" (GDPs) in intracellular recordings in vitro. GABA, the major inhibitory neurotransmitter of the adult brain, has a depolarizing action in immature neurons, and GDPs have been proposed to be driven by GABAergic transmission. Moreover, GDPs have been thought to reflect an early pattern that disappears during development in parallel with the maturation of hyperpolarizing GABAergic inhibition. However, the adult hippocampus in vivo also generates endogenous network events known as sharp (positive) waves (SPWs), which reflect synchronous discharges of CA3 pyramidal neurons and are thought to be involved in cognitive functions. In this thesis, mechanisms of GDP generation were studied with intra- and extracellular recordings in the neonatal rat hippocampus in vitro and in vivo. Immature CA3 pyramidal neurons were found to generate intrinsic bursts of spikes and to act as cellular pacemakers for GDP activity whereas depolarizing GABAergic signalling was found to have a temporally non-patterned facilitatory role in the generation of the network events. Furthermore, the data indicate that the intrinsic bursts of neonatal CA3 pyramidal neurons and, consequently, GDPs are driven by a persistent Na+ current and terminated by a slow Ca2+-dependent K+ current. Gramicidin-perforated patch recordings showed that the depolarizing driving force for GABAA receptor-mediated actions is provided by Cl- uptake via the Na-K-C1 cotransporter, NKCC1, in the immature CA3 pyramids. A specific blocker of NKCC1, bumetanide, inhibited SPWs and GDPs in the neonatal rat hippocampus in vivo and in vitro, respectively. Finally, pharmacological blockade of the GABA transporter-1 prolonged the decay of the large GDP-associated GABA transients but not of single postsynaptic GABAA receptor-mediated currents. As a whole the data in this thesis indicate that the mechanism of GDP generation, based on the interconnected network of bursting CA3 pyramidal neurons, is similar to that involved in adult SPW activity. Hence, GDPs do not reflect a network pattern that disappears during development but they are the in vitro counterpart of neonatal SPWs.

Molecular mechanisms of cancer predisposition in HNPCC/Lynch syndrome

Hereditary non-polyposis colorectal carcinoma (HNPCC; Lynch syndrome) is among the most common hereditary cancers in man and a model of cancers arising through deficient DNA mismatch repair (MMR). It is inherited in a dominant manner with predisposing germline mutations in the MMR genes, mainly MLH1, MSH2, MSH6 and PMS2. Both copies of the MMR gene need to be inactivated for cancer development. Since Lynch syndrome family members are born with one defective copy of one of the MMR genes in their germline, they only need to acquire a so called second hit to inactivate the MMR gene. Hence, they usually develop cancer at an early age. MMR gene inactivation leads to accumulation of mutations particularly in short repeat tracts, known as microsatellites, causing microsatellite instability (MSI). MSI is the hallmark of Lynch syndrome tumors, but is present in approximately 15% of sporadic tumors as well. There are several possible mechanisms of somatic inactivation (i.e. the second hit ) of MMR genes, for instance deletion of the wild-type copy, leading to loss of heterozygosity (LOH), methylation of promoter regions necessary for gene transcription, or mitotic recombination or gene conversion. In the Lynch syndrome tumors carrying germline mutations in the MMR gene, LOH was found to be the most frequent mechanism of somatic inactivation in the present study. We also studied MLH1/MSH2 deletion carriers and found that somatic mutations identical to the ones in the germline occurred frequently in colorectal cancers and were also present in extracolonic Lynch syndrome-associated tumors. Chromosome-specific marker analysis implied that gene conversion, rather than mitotic recombination or deletion of the respective gene locus accounted for wild-type inactivation. Lynch syndrome patients are predisposed to certain types of cancers, the most common ones being colorectal, endometrial and gastric cancer. Gastric cancer and uroepithelial tumors of bladder and ureter were observed to be true Lynch syndrome tumors with MMR deficiency as the driving force of tumorigenesis. Brain tumors and kidney carcinoma, on the other hand, were mostly MSS, implying the possibility of alternative routes of tumor development. These results present possible implications in clinical cancer surveillance. In about one-third of families suspected of Lynch syndrome, mutations in MMR genes are not found, and we therefore looked for alternative mechanisms of predisposition. According to our results, large genomic deletions, mainly in MSH2, and germline epimutations in MLH1, together explain a significant fraction of point mutation-negative families suspected of Lynch syndrome and are associated with characteristic clinical and family features. Our findings have important implications in the diagnosis and management of Lynch syndrome families.

Ternary metal complexes of anionic and neutral pyridoxine (vitamin B6) with 2,2'-bipyridine. Syntheses and x-ray structures of (pyridoxinato)bis(2,2'-bipyridyl)cobalt(III) perchlorate and chloro(2,2'-bipyridyl)(pyridoxine)copper(II) perchlorate hydrate

Ternary metal complexes involving vitamin B6 with formulas [CO",(PN-H)](anCdI [OC)'(bpy)(PN)Cl]C10(.bpHy 0 = 2,2'-bipyridine, PN = neutral pyridoxine, PN-H = anionic pyridoxine) have been prepared for the first time and characterized by means of magnetic and spectroscopic measurements. The crystal structures of the compounds have also been determined. [CO(PN-H)](CcryIsOta,l)lize s in the space group P2,/c with a = 18.900 (3) A, b = 8.764 (1) A, c = 20.041 (2) A,p = 116.05 (l)', and Z = 4 and [Cu(bpy)(PN)C1]C104-H20in the space group Pi with a = 12.136 (5) A, b = 13.283 (4) A,c = 7.195 (2) A, a = 96.91 (Z)', 0 = 91.25 (3)', y = 71.63 (3)', and Z = 2. The structures were solved by the heavy-atom method and refined by least-squares techniques to R values of 0.080 and 0.042 for 3401 and 2094 independent reflections, respectively. Both structures consist of monomeric units. The geometry around Co(II1) is octahedral and around Cu(I1) is distorted square pyramidal. In [CO(PN-H)]t(wCo IoxOy~ge)n~s ,fro m phenolic and 4-(hydroxymethyl) groups of PN-H and two nitrogens from each of two bpy's form the coordination sphere. In [Cu(bpy)(PN)C1]C104.H20o ne PN and one bpy, with the same donor sites, act as bidentate chelates in the basal plane, with a chloride ion occupying the apical position. In both structures PN and PN-H exist in the tautomeric form wherein pyridine N is protonated and phenolic 0 is deprotonated. However, a novel feature of the cobalt compound is that PN-H is anionic due to the deprotonation of the 4-(hydroxymethyl) group. The packing in both structures is governed by hydrogen bonds, and in the copper compound partial stacking of bpy's at a distance of -3.55 also adds to the stability of the system. Infrared, NMR, and ligand field spectroscopic results and magnetic measurements are interpreted in light of the structures.

Detection and differentiation of bovine herpesvirus 1 and 5 using a multiplex real-time polymerase chain reaction.

A multiplex real-time PCR was developed for the detection and differentiation of two closely related bovine herpesviruses 1 (BoHV-1) and 5 (BoHV-5). The multiplex real-time PCR combines a duplex real-time PCR that targets the DNA polymerase gene of BoHV-1 and BoHV-5 and a real-time PCR targeting mitochondrial DNA, as a house-keeping gene, described previously by Cawthraw et al. (2009). The assay correctly identified 22 BoHV-1 and six BoHV-5 isolates from the Biosecurity Sciences Laboratory virus collection. BoHV-1 and BoHV-5 were also correctly identified when incorporated in spiked semen and brain tissue samples. The detection limits of the duplex assay were 10 copies of BoHV-1 and 45 copies of BoHV-5. The multiplex real-time PCR had reaction efficiencies of 1.04 for BoHV-1 and 1.08 for BoHV-5. Standard curves relating Ct value to template copy number had correlation coefficients of 0.989 for BoHV-1 and 0.978 for BoHV-5. The assay specificity was demonstrated by testing bacterial and viral DNA from pathogens commonly isolated from bovine respiratory and reproductive tracts. The validated multiplex real-time PCR was used to detect and differentiate BoHV-1 and BoHV-5 in bovine clinical samples with known histories.